Lung cancer is the leading cause of cancer mortality and lung adenocarcinoma (LUAD) accounts for more than half of all lung cancer cases. Tumor elimination is mostly hindered by drug resistance and the mechanisms remain to be explored in LUAD. CRISPR screens in cell and murine models and single-cell RNA sequencing were conducted, which identified MAF bZIP transcription factor F (MAFF) as a critical factor regulating tumor growth and treatment resistance in LUAD. RNA and ChIP sequencing analyses were performed for transcriptional target expression and specific binding sites of MAFF. Functions of MAFF in inhibiting tumor growth and promoting cisplatin or irradiation efficacy were investigated using cellular and xenograft models. Patients with lung adenocarcinoma and reduced MAFF expression had worse clinical outcomes. MAFF inhibited tumor cell proliferation by regulating the expression of SLC7A11, CDK6, and CDKN2C, promoting ferroptosis and preventing cell cycle progression from G1 to S. MAFF also conferred tumor cells vulnerable to cisplatin-based or ionizing radiation treatments. MAFF reduction was a final event in the acquisition of cisplatin resistance of LUAD cells. The intracellular cAMP/PKA/CREB1 pathway upregulated MAFF in response to cisplatin-based or ionizing radiation treatments. MAFF suppresses tumor growth, and pharmacological agonists targeting MAFF may improve cisplatin or irradiation therapies for lung adenocarcinoma patients.

中文翻译：

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MAFF 通过调节肺腺癌的铁死亡和细胞周期进展，赋予基于顺铂和电离辐射治疗的脆弱性


肺癌是癌症死亡的主要原因，肺腺癌 (LUAD) 占所有肺癌病例的一半以上。肿瘤消除主要受到耐药性的阻碍，LUAD 的机制仍有待探索。在细胞和小鼠模型中进行 CRISPR 筛选以及单细胞 RNA 测序，确定 MAF bZIP 转录因子 F (MAFF) 是调节 LUAD 肿瘤生长和治疗耐药性的关键因素。对 MAFF 的转录靶表达和特异性结合位点进行 RNA 和 ChIP 测序分析。使用细胞和异种移植模型研究了 MAFF 在抑制肿瘤生长和促进顺铂或放射疗效方面的功能。 MAFF 表达减少的肺腺癌患者的临床结果较差。 MAFF 通过调节 SLC7A11、CDK6 和 CDKN2C 的表达来抑制肿瘤细胞增殖，促进铁死亡并阻止细胞周期从 G1 进展到 S。MAFF 还使肿瘤细胞容易受到基于顺铂或电离放射治疗的影响。 MAFF 减少是 LUAD 细胞获得顺铂耐药性的最终事件。细胞内 cAMP/PKA/CREB1 通路响应顺铂或电离放射治疗而上调 MAFF。 MAFF 抑制肿瘤生长，针对 MAFF 的药理学激动剂可能会改善肺腺癌患者的顺铂或放射治疗。